Lin Che, Jing Huang, Jin-Xian Lin, Chi-Yu Xu, Xin-Mou Wu, Ze-Bang Du, Jia-Shen Wu, Zhong-Ning Lin, Yu-Chun Lin
{"title":"黄曲霉毒素B1暴露通过p53和periilipin 2相互作用介导的线粒体-脂滴接触触发肝脏脂肪毒性:体外和体内评估。","authors":"Lin Che, Jing Huang, Jin-Xian Lin, Chi-Yu Xu, Xin-Mou Wu, Ze-Bang Du, Jia-Shen Wu, Zhong-Ning Lin, Yu-Chun Lin","doi":"10.1016/j.jhazmat.2022.130584","DOIUrl":null,"url":null,"abstract":"<p><p>Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins widely found in food contaminants, and its target organ is the liver. It poses a major food security and public health threat worldwide. However, the lipotoxicity mechanism of AFB1 exposure-induced liver injury remains unclear and requires further elucidation. Herein, we investigated the potential hepatic lipotoxicity of AFB1 exposure using in vitro and in vivo models to assess the public health hazards of high dietary AFB1 exposure. We demonstrated that low-dose of AFB1 (1.25 μM for 48 h, about one-fifth of the IC50 in HepG2 and HepaRG cells, IC50 are 5.995 μM and 5.266 μM, respectively) exposure significantly induced hepatic lipotoxicity, including abnormal lipid droplets (LDs) growth, mitochondria-LDs contacts increase, lipophagy disruption, and lipid accumulation. Mechanistically, we showed that AFB1 exposure promoted the mitochondrial p53 (mito-p53) and LDs-associated protein perilipin 2 (PLIN2) interaction-mediated mitochondria-LDs contacts, resulting in lipid accumulation in hepatocytes. Mito-p53-targeted inhibition, knockdown of PLIN2, and rapamycin application efficiently promoted the lysosome-dependent lipophagy and alleviated the hepatic lipotoxicity and liver injury induced by AFB1 exposure. Overall, our study found that mito-p53 and PLIN2 interaction mediates three organelles-mitochondria, LDs, and lysosomal networks to regulate lipid homeostasis in AFB1 exposure-induced hepatotoxicity, revealing how this unique trio of organelles works together and provides a novel insight into the targeted intervention in inter-organelle lipid sensing and trafficking for alleviating hazardous materials-induced hepatic lipotoxicity.</p>","PeriodicalId":361,"journal":{"name":"Journal of Hazardous Materials","volume":null,"pages":null},"PeriodicalIF":12.2000,"publicationDate":"2023-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"4","resultStr":"{\"title\":\"Aflatoxin B1 exposure triggers hepatic lipotoxicity via p53 and perilipin 2 interaction-mediated mitochondria-lipid droplet contacts: An in vitro and in vivo assessment.\",\"authors\":\"Lin Che, Jing Huang, Jin-Xian Lin, Chi-Yu Xu, Xin-Mou Wu, Ze-Bang Du, Jia-Shen Wu, Zhong-Ning Lin, Yu-Chun Lin\",\"doi\":\"10.1016/j.jhazmat.2022.130584\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins widely found in food contaminants, and its target organ is the liver. It poses a major food security and public health threat worldwide. However, the lipotoxicity mechanism of AFB1 exposure-induced liver injury remains unclear and requires further elucidation. Herein, we investigated the potential hepatic lipotoxicity of AFB1 exposure using in vitro and in vivo models to assess the public health hazards of high dietary AFB1 exposure. We demonstrated that low-dose of AFB1 (1.25 μM for 48 h, about one-fifth of the IC50 in HepG2 and HepaRG cells, IC50 are 5.995 μM and 5.266 μM, respectively) exposure significantly induced hepatic lipotoxicity, including abnormal lipid droplets (LDs) growth, mitochondria-LDs contacts increase, lipophagy disruption, and lipid accumulation. Mechanistically, we showed that AFB1 exposure promoted the mitochondrial p53 (mito-p53) and LDs-associated protein perilipin 2 (PLIN2) interaction-mediated mitochondria-LDs contacts, resulting in lipid accumulation in hepatocytes. Mito-p53-targeted inhibition, knockdown of PLIN2, and rapamycin application efficiently promoted the lysosome-dependent lipophagy and alleviated the hepatic lipotoxicity and liver injury induced by AFB1 exposure. Overall, our study found that mito-p53 and PLIN2 interaction mediates three organelles-mitochondria, LDs, and lysosomal networks to regulate lipid homeostasis in AFB1 exposure-induced hepatotoxicity, revealing how this unique trio of organelles works together and provides a novel insight into the targeted intervention in inter-organelle lipid sensing and trafficking for alleviating hazardous materials-induced hepatic lipotoxicity.</p>\",\"PeriodicalId\":361,\"journal\":{\"name\":\"Journal of Hazardous Materials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.2000,\"publicationDate\":\"2023-03-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Hazardous Materials\",\"FirstCategoryId\":\"93\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jhazmat.2022.130584\",\"RegionNum\":1,\"RegionCategory\":\"环境科学与生态学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENGINEERING, ENVIRONMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Hazardous Materials","FirstCategoryId":"93","ListUrlMain":"https://doi.org/10.1016/j.jhazmat.2022.130584","RegionNum":1,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, ENVIRONMENTAL","Score":null,"Total":0}
Aflatoxin B1 exposure triggers hepatic lipotoxicity via p53 and perilipin 2 interaction-mediated mitochondria-lipid droplet contacts: An in vitro and in vivo assessment.
Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins widely found in food contaminants, and its target organ is the liver. It poses a major food security and public health threat worldwide. However, the lipotoxicity mechanism of AFB1 exposure-induced liver injury remains unclear and requires further elucidation. Herein, we investigated the potential hepatic lipotoxicity of AFB1 exposure using in vitro and in vivo models to assess the public health hazards of high dietary AFB1 exposure. We demonstrated that low-dose of AFB1 (1.25 μM for 48 h, about one-fifth of the IC50 in HepG2 and HepaRG cells, IC50 are 5.995 μM and 5.266 μM, respectively) exposure significantly induced hepatic lipotoxicity, including abnormal lipid droplets (LDs) growth, mitochondria-LDs contacts increase, lipophagy disruption, and lipid accumulation. Mechanistically, we showed that AFB1 exposure promoted the mitochondrial p53 (mito-p53) and LDs-associated protein perilipin 2 (PLIN2) interaction-mediated mitochondria-LDs contacts, resulting in lipid accumulation in hepatocytes. Mito-p53-targeted inhibition, knockdown of PLIN2, and rapamycin application efficiently promoted the lysosome-dependent lipophagy and alleviated the hepatic lipotoxicity and liver injury induced by AFB1 exposure. Overall, our study found that mito-p53 and PLIN2 interaction mediates three organelles-mitochondria, LDs, and lysosomal networks to regulate lipid homeostasis in AFB1 exposure-induced hepatotoxicity, revealing how this unique trio of organelles works together and provides a novel insight into the targeted intervention in inter-organelle lipid sensing and trafficking for alleviating hazardous materials-induced hepatic lipotoxicity.
期刊介绍:
The Journal of Hazardous Materials serves as a global platform for promoting cutting-edge research in the field of Environmental Science and Engineering. Our publication features a wide range of articles, including full-length research papers, review articles, and perspectives, with the aim of enhancing our understanding of the dangers and risks associated with various materials concerning public health and the environment. It is important to note that the term "environmental contaminants" refers specifically to substances that pose hazardous effects through contamination, while excluding those that do not have such impacts on the environment or human health. Moreover, we emphasize the distinction between wastes and hazardous materials in order to provide further clarity on the scope of the journal. We have a keen interest in exploring specific compounds and microbial agents that have adverse effects on the environment.